1. High Frequency Ventilation in PPHN Namasivayam Ambalavanan M.D. Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham

2. Overview of presentation Introduction to PPHN Introduction to PPHN Types of HFV Types of HFV Hyperventilation in PPHN Hyperventilation in PPHN HFOV, HFJV, and HFFI trials HFOV, HFJV, and HFFI trials HFV techniques HFV techniques

3. What is the problem? PPHN / PFC : persistence of the pattern of fetal circulation postnatally due to a sustained elevation of pulmonary vascular resistance, with right-to-left shunt at the ductus arteriosus or foramen ovale in the absence of structural heart disease PPHN / PFC : persistence of the pattern of fetal circulation postnatally due to a sustained elevation of pulmonary vascular resistance, with right-to-left shunt at the ductus arteriosus or foramen ovale in the absence of structural heart disease Incidence:1: 522-1454. Exact incidence unknown in the absence of ICD coding or a “gold standard” for diagnosis Incidence:1: 522-1454. Exact incidence unknown in the absence of ICD coding or a “gold standard” for diagnosis Mortality and morbidity: mortality > 50% in the absence of ECMO, and >10-20% with ECMO; >20% severe handicap/intracranial hemorrhage/deafness Mortality and morbidity: mortality > 50% in the absence of ECMO, and >10-20% with ECMO; >20% severe handicap/intracranial hemorrhage/deafness (Walsh-Sukys. Clin Perinatol 20: 127-143, 1993)

4. Causes of PPHN (Geggel RL, Reid LM: (Geggel RL, Reid LM: Clin Perinatol 11:525, 1984) Clin Perinatol 11:525, 1984) PPHN Normal Arterial Number Decreased Arteries e.g. CDH Normal muscularization Increased muscularization Developmental immaturity Maladaptation due to acute injury (commonest) e.g. Sepsis, MAS, asphyxia Chronic injury with vascular remodeling Malform- ation

5. Current management Confirm diagnosis of PPHN Correct underlying abnormalities (hypothermia, acidosis, hypocalcemia, hypoglycemia, polycythemia) Conservative mechanical ventilation Trial of hyperventilation If low PO2, trial of rescue therapies MetabolicHFV SurfactantVasodilators ECMO Alkalosis NO, PGD 2, PGI 2, Tolazoline, Adenosine

6. Pathophysiological basis of current management Mechanical ventilation: Mechanical ventilation:  V/Q matching to improve oxygenation  respiratory alkalosis to reduce PVR Metabolic alkalosis: effect of pH on PVR Metabolic alkalosis: effect of pH on PVR Vasodilators: specific relaxation of the pulmonary vasculature. Most experience with NO. Vasodilators: specific relaxation of the pulmonary vasculature. Most experience with NO. ECMO: modified long-term cardio-pulmonary bypass ECMO: modified long-term cardio-pulmonary bypass

7. High frequency ventilation Techniques Techniques HFPPV HFJV HFFIHFOV HFPPV HFJV HFFIHFOV V T >dead sp > or or dead sp > or or <ds <ds Exp passive passive passive active Wave- variable triangular triangular sine wave form Entrai- none possible nonenone ment Freq. 60-150 60-600 300-900 300-3000 (60-80) (350-450) (480-720) (600-900) (/min)

8. High frequency ventilation HFPPV HFPPV  conventional ventilators with low-compliance tubing  ventilatory rates of 60-150/min  not very effective: minute ventilation decreases with high frequencies [If T I < 3 TC, V T decreases.] (Boros et al. Pediatrics 74: 487-492, 1984 )  ventilator and circuit design are not optimal for use at frequencies

9. High frequency ventilation HFJV (e.g. Bunnell Life Pulse HFJV) HFJV (e.g. Bunnell Life Pulse HFJV)  adequate gas exchange with lower MAP  Servo pressure reflects volume ventilated:  increases with improving compliance or resistance or by peri-ET leaks  decreased by worsening compliance, resistance, obstruction, or pneumothorax  Larger babies: 300 bpm; smaller ones: 500 bpm

10. High frequency ventilation HFJV (contd.) HFJV (contd.)  MAP controls PaO 2,  P (and frequency) controls PaCO 2 (MAP controls lung volume. PaO 2 will not respond to increased MAP if FRC normal)  smaller V T (  P) with higher PEEP better than larger V T with lower PEEP (--> hypoxia with hypocarbia)  Optimal PEEP: no drop in SpO 2 when CMV off  Parallel conventional ventilation recruits alveoli (use low rate : 1-3 bpm; 0-1 bpm if air leak)

11. High frequency ventilation HFOV (e.g. Sensormedics 3100A) HFOV (e.g. Sensormedics 3100A)  MAP controls PaO 2, amplitude (and frequency) control PaCO 2  Optimal MAP difficult to determine as CXR “rib space counting” not accurate (Thome et al. Pediatr Pulmonol 26:265-72, 1998)  Frequency: 5-10 Hz better for CO 2 elimination; 10-15 Hz better for improving oxygenation  maybe useful in airleak syndromes  maybe useful in PPHN; may decrease need for ECMO esp. if combined with NO

12. High frequency ventilation HFFI (e.g. Infant Star with HFFI module) HFFI (e.g. Infant Star with HFFI module)  active expiration in Infant Star model makes operation more like HFOV  MAP controls PaO 2, amplitude (and frequency) controls PaCO 2  insufficient evidence to show it to be superior to conventional ventilation  more convenient: single ventilator for CMV and HFV makes initiation and weaning easier

13. High Frequency Ventilation in PPHN V/Q matching to improve oxygenation V/Q matching to improve oxygenation Respiratory alkalosis to reduce PVR Respiratory alkalosis to reduce PVR Improved response to inhaled NO Improved response to inhaled NO “Rescue” for air leak syndromes “Rescue” for air leak syndromes

14. Hyperventilation in PPHN No HV/Alk HV Alk HV+Alk p No HV/Alk HV Alk HV+Alk p Mortality% 4.4 6.8 9.5 9.80.67 ECMO% 33.313.644.6 34.20.008 Duration 7.8 7.2 7.8 12.60.0013 ventilator (d) Duration O 2 (d) 11.111.5 11.9 17.5 0.001 O 2 at 28 d 2.7 2.8 6.8 16.7 0.1 (Walsh-Sukys et al. Pediatrics 105:14-20, 2000)

15. HFOV in term infants Early studies: Early studies: Kohelet et al. Crit Care Med 16: 510-6, 1988  HFOV in 41 infants with PPHN  34 showed improved oxygenation and ventilation, and decreasing MAP Carter et al. Pediatrics 85: 159-64, 1990  50 ECMO referrals with A-a O 2 >600. 4 died early.  21 responded to HFOV and did not require ECMO  25 needed ECMO, with more morbidity & 3 died.  Infants responding to HFOV more often had pneumonia

16. HFOV in term infants Varnholt et al. Eur J Pediatr 151: 769-74, 1992 HFOV tried in 50 infants meeting ECMO criteria HFOV tried in 50 infants meeting ECMO criteria 25 responded to HFOV, 25 needed ECMO 25 responded to HFOV, 25 needed ECMO 2 responders subsequently needed ECMO due to air leaks 2 responders subsequently needed ECMO due to air leaks Responders in Carter’s and Varnholt’s study tended to be younger (37-38 wks vs. 39-40 wks)

17. HFOV in term infants Recent studies: Recent studies: Clark et al. J Pediatr 124: 447-54, 1994 GA >34 w, B.wt> 2 kg, 34 w, B.wt> 2 kg, < 14 d age on high vent settings 81 neonates randomized to HFOV or CV 81 neonates randomized to HFOV or CV Patients stratified before admission based on primary diagnosis (pneumonia, MAS, RDS, air leak, or other) Patients stratified before admission based on primary diagnosis (pneumonia, MAS, RDS, air leak, or other)

18. HFOV in term infants Clark et al contd. Mortality: HFOV 1/39 vs. CV 2/40 Mortality: HFOV 1/39 vs. CV 2/40 ECMO need: HFOV: 12/39 vs. CV 6/40 (n.s) ECMO need: HFOV: 12/39 vs. CV 6/40 (n.s) Median days on ventilator: 8 in both groups Median days on ventilator: 8 in both groups O 2 reqt at 28 days: HFOV 11/39 vs. CV 5/40 (n.s.) O 2 reqt at 28 days: HFOV 11/39 vs. CV 5/40 (n.s.) This trial was prematurely terminated (needed 250) and hence did not have enough power

19. HFJV in term infants Carlo et al. Am J Dis Child 143: 233-8, 1989 14 infants on HFJV compared to 23 infants on CV 14 infants on HFJV compared to 23 infants on CV HFJV: reduction in MAP and PaCO 2 HFJV: reduction in MAP and PaCO 2 No change in mortality, A-aDO 2, air leaks, BPD, duration of ventilation or O 2 supplementation No change in mortality, A-aDO 2, air leaks, BPD, duration of ventilation or O 2 supplementation This was a small pilot study, not a randomized trial This was a small pilot study, not a randomized trial Peters et al. J Perinatol 12: 21-4, 1992 2 infants with pulmonary hypoplasia and PPHN worsening on CV survived on HFJV 2 infants with pulmonary hypoplasia and PPHN worsening on CV survived on HFJV

20. HFJV in term infants Engle et al. J Perinatol 17:3-9, 1997 Small RCT of HFJV (n=11) vs. HFPPV Small RCT of HFJV (n=11) vs. HFPPV HFJV: Stable MAP and PIP. Improved oxygenation, ventilation, and OI HFJV: Stable MAP and PIP. Improved oxygenation, ventilation, and OI HFPPV: Required higher PIP to maintain same oxygenation, ventilation, and OI. HFPPV: Required higher PIP to maintain same oxygenation, ventilation, and OI. No difference in survival without ECMO, duration of ventilation, O2, hospital stay, need for ECMO, or BPD. No difference in survival without ECMO, duration of ventilation, O2, hospital stay, need for ECMO, or BPD.

21. HFJV Stewart et al. Eur Respir J 9:1257-60, 1996 30 infants meeting criteria for ECMO 30 infants meeting criteria for ECMO 22 responded to HFJV, 8 non-responders required ECMO 22 responded to HFJV, 8 non-responders required ECMO Responders showed a decrease in OI without increases in MAP within 4 hours Responders showed a decrease in OI without increases in MAP within 4 hours Same problem of small sample size, uncontrolled observational report Same problem of small sample size, uncontrolled observational report Many similar uncontrolled studies and case series exist on HFJV, but only a few controlled trials in term infants.

22. HFFI in term infants Very few trials of HFFI in term infants Very few trials of HFFI in term infants Jirapaet et al. Respir Care 46: 586-94, 2001 36 infants with PPHN requiring hyperventilation and FiO 2 1.0 with PaO 2 < 60 torr. HFFI (n=18) or CV (n=18) in non-randomized manner. 36 infants with PPHN requiring hyperventilation and FiO 2 1.0 with PaO 2 < 60 torr. HFFI (n=18) or CV (n=18) in non-randomized manner. HFFI: HFFI:  Survival 78% vs. 44% on CV (p=0.087)  Less chronic lung disease (1 vs. 5, p 0.02)  Faster extubation (8.1 vs. 18.7 d, p 0.03)  Improvements in other respiratory variables (less hypocarbia and alkalosis, improved oxygenation)

23. Comparison of HFV techniques No human comparisons No human comparisons Wiswell et al. Am J Dis Child 146: 1287-93, 1992 56 newborn piglets with meconium instillation 56 newborn piglets with meconium instillation Randomized to CV, HFJV, or HFFI for 6 hours Randomized to CV, HFJV, or HFFI for 6 hours Measures of oxygenation mostly similar Measures of oxygenation mostly similar Lung histologic changes worse on CV compared to HFJV or HFFI Lung histologic changes worse on CV compared to HFJV or HFFI Simma et al. Pediatr Pulmonol 22: 263, 1996 More lung injury in animals treated with HFV+CV than HFOV alone More lung injury in animals treated with HFV+CV than HFOV alone

24. Comparison of HFV techniques Bancalari et al. J Pediatr 110-617-22, 1987 Animals on HFOV vs. HFJV Animals on HFOV vs. HFJV More air trapping on HFJV (due to active exhalation on HFOV?) More air trapping on HFJV (due to active exhalation on HFOV?) Many centers now use HFOV for term infants with PPHN, rather than HFFI or HFJV Not possible to state if one type of HFV is better in human infants

25. HFV Indications Usually used as “rescue” therapy for infants not improving/deteriorating on conventional ventilator Usually used as “rescue” therapy for infants not improving/deteriorating on conventional ventilator Response to HFJV or HFOV may depend on disease pathophysiology: Response to HFJV or HFOV may depend on disease pathophysiology:  Pneumonia and RDS more likely to respond (70-90%)  MAS (50%) and CDH (20%) less likely to respond (Baumgart et al. Pediatrics 89:491, 1992; Paranka et al. Pediatrics 95: 400, 1995; Stewart et al. Eur Respir J 9:1257, 1996)

26. HFV techniques HFOV, usually with Sensormedics 3100 HFOV, usually with Sensormedics 3100 MAP: 1-3 cm H 2 O higher than on IMV MAP: 1-3 cm H 2 O higher than on IMV Frequency: 10-12 Hz Frequency: 10-12 Hz Inspiratory time: 33% Inspiratory time: 33% Amplitude: sufficient for visible chest motion Amplitude: sufficient for visible chest motion Target ABG: pH 7.45-7.55, PaCO 2 30-40, PaO 2 80-100, HCO 3 26-30 Target ABG: pH 7.45-7.55, PaCO 2 30-40, PaO 2 80-100, HCO 3 26-30

27. HFV techniques “High volume strategy” often used “High volume strategy” often used  Useful in animal models and preterm infants with RDS  Assessment of lung volume a problem (chest X-Rays not accurate)  Initial MAP 10-20% more than MAP on IMV.  Increase MAP in 1-3 cm H 2 O increments until oxygenation and a/A ratio improve or cardiac compromise occurs  FiO 2 can then be weaned. As lungs improve, wean MAP slowly (MAP changes may take > 1 hr to affect PaO 2 )

28. HFV + NO The combination of HFOV and NO is more effective than HFOV alone or NO alone The combination of HFOV and NO is more effective than HFOV alone or NO alone Kinsella et al. J Pediatr 131: 55-62, 1997 Mulicenter RCT on PPHN with n=205 Mulicenter RCT on PPHN with n=205 Randomized to IMV+NO or HFOV alone Randomized to IMV+NO or HFOV alone If PaO 2 <60, cross-over to other therapy If PaO 2 <60, cross-over to other therapy If PaO 2 still <60, HFOV+NO If PaO 2 still <60, HFOV+NO Treatment success if PaO 2 >60 sustained Treatment success if PaO 2 >60 sustained

29. HFV + NO Kinsella et al contd. 28% responded to NO, 23% to HFOV (100% survival and similar outcome in responders) 28% responded to NO, 23% to HFOV (100% survival and similar outcome in responders) Non-responders following crossover: 21% responded to NO, and 14% to HFOV Non-responders following crossover: 21% responded to NO, and 14% to HFOV 125 did not respond to either NO or HFOV alone: 32% responded to HFOV+NO 125 did not respond to either NO or HFOV alone: 32% responded to HFOV+NO Combination works better for those with significant parenchymal lung disease (e.g. MAS, RDS) Combination works better for those with significant parenchymal lung disease (e.g. MAS, RDS)

30. HFV + Surfactant Surfactant: Surfactant:  inactivation in MAS and pneumonia  deficiency in RDS and CDH Animal studies Animal studies  HFV does not affect delivery of bolus surfactant (Heldt et al. Pediatr Res 31:270, 1992; Walther et al. Pediatr Res 22:725, 1987)  HFV and surfactant prevent lung injury synergistically (Jackson et al. Am J Respir Crit Care Med 150: 534, 1994)

31. HFV + Surfactant Survanta in term infants study group: Survanta in term infants study group:  Multicenter RCT on infants at risk for ECMO  Surfactant use may reduce need for ECMO, especially when used early (OI 15-22) (Lotze et al. J Pediatr (Lotze et al. J Pediatr 132:40-7, 1998) Surfactant in MAS: Surfactant in MAS:  1/20 in surfactant gp vs. 6/20 controls needed ECMO  0/20 in surfactant gp vs. 5/20 controls had air leaks (Findlay et al. Pediatrics 97: 48-52, 1996)

32. HFV + Surfactant No studies focusing on HFV + Surfactant in term neonates No studies focusing on HFV + Surfactant in term neonates Studies in preterm neonates indicate that HFV: Studies in preterm neonates indicate that HFV:  prolongs efficacy of surfactant  reduces number of surfactant doses  reduces pulmonary morbidity (Gerstmann et al. Pediatrics 98:1044, 1996; Clark and Gerstman. Clin Perinatol 25: 113-122, 1998)

33. Does HFV “rescue” prevent ECMO but lead to more chronic lung disease? Vaucher et al. J Pediatr 128: 109, 1996 ECMO survivors vs. avoiders: less CLD, shorter ventilation and hospital stay ECMO survivors vs. avoiders: less CLD, shorter ventilation and hospital stay Walsh-Sukys et al. J Pediatr 125: 104, 1994 ECMO survivors vs. avoiders: less CLD, less rehospitalizations ECMO survivors vs. avoiders: less CLD, less rehospitalizationshowever, Schwendeman et al. Crit Care Med 20: 372, 1992 ECMO avoiders had less CLD and neurologic morbidity ECMO avoiders had less CLD and neurologic morbidity

34. Impact of HFV: more recent reports Reduction in ECMO use by HFV + NO Reduction in ECMO use by HFV + NO  Magnitude of reduction ranges from 40 to 75%, depending on center  Reduction of ECMO use not associated with longer ECMO in those needing it Shorter hospitalization, lower costs Shorter hospitalization, lower costs (Kennaugh et al. J Perinatol 17: 366-9, 1997; Kachel et al. Int J Artif Organs 18: 589-97, 1995; Hintz et al. Pediatrics 106: 1339- 43, 2000)

35. The current situation: Despite common use of HFV, there is insufficient data from randomized controlled trials to support the routine use of rescue HFV in term infants with PPHN